Asymmetric Hydrogenation of Disubstituted, Trisubstituted, and Tetrasubstituted Minimally Functionalized Olefins and Cyclic β-Enamides with Easily Accessible Ir-P,Oxazoline Catalysts

Article abstract of DOI:10.1021/acscatal.8b03170

We have developed a family of Ir-P,oxazoline catalysts for asymmetric hydrogenation. These catalysts, with a simple modular architecture, have shown a high tolerance to the olefin geometry and substitution pattern, and to the presence of several neighboring polar groups. Thus, they were able to successfully hydrogenate disubstituted, trisubstituted, and tetrasubstituted minimally functionalized olefins (with enantiomeric excess values up to 99%). The excellent catalytic performance was also extended to the hydrogenation of cyclic β-enamides.

Full text of DOI:10.1021/acscatal.8b03170

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Letter
Asymmetric hydrogenation of di-, tri- and tetrasubstituted
minimally functionalized olefins and cyclic #-
enamides with easily accessible Ir-P,oxazoline catalysts
Maria Biosca, Marc Magre, Oscar Pàmies, and Montserrat Diéguez
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b03170 • Publication Date (Web): 02 Oct 2018
Downloaded from http://pubs.acs.org on October 2, 2018
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Asymmetric hydrogenation of di-, tri- and tetrasubstituted minimal-
ly functionalized olefins and cyclic β-enamides with easily accessible
Ir-P,oxazoline catalysts.
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Maria Biosca, Marc Magre, Oscar Pàmies* and Montserrat Diéguez*
Universitat Rovira i Virgili. Departament de Química Física i Inorgànica. C/ Marcel·lí Domingo 1, 43007 Tarragona,
Spain.
ABSTRACT: We have developed a family of Ir-P,oxazoline catalysts for asymmetric hydrogenation. These catalysts, with a
simple modular architecture, have shown a high tolerance to the olefin geometry and substitution pattern, and to the
presence of several neighboring polar groups. Thus, they were able to successfully hydrogenate di-, tri- and tetrasubstitut-
ed minimally functionalized olefins (ee's up to 99%). The excellent catalytic performance was also extended to the hydro-
genation of cyclic β-enamides.
KEYWORDS: Iridium, P,N-ligands, asymmetric hydrogenation, unfunctionalized olefins, cyclic β-enamides.
Asymmetric hydrogenation (AH) of olefins is a well-
known approach to introduce chirality into target mole-
cules. It has perfect atom economy, uses low catalyst
loading and it is operationally simple.1 The AH of func-
tionalized olefins has been thoroughly studied for dec-
ades and can now be considered a mature field.2 Rh- and
Ru-catalysts, mostly based on diphosphine ligands have
performed the best. Their performance is critically influ-
enced by the substrate coordinative groups that guide the
chiral transfer to the product. When those coordinative
groups are absent (minimally functionalized olefins), the
introduction of chirality becomes a much greater chal-
lenge and, in this field, Ir-catalysts have performed the
best.3 The best catalysts have two characteristics in com-
mon: (i) they contain P,N ligands and (ii) their optimal
structure is highly dependent on the geometry and substi-
tution pattern of the olefin.3 The consequence is that for
each particular olefin type a different ligand family needs
to be developed. Figure 1 shows a selection of the most
efficient chiral ligands and illustrates how different the
ligand motifs need to be to achieve high enantioselectivity
for each particular olefin substitution pattern. It is also
important to notice that different degrees of catalyst de-
velopment have been achieved for each olefin substitu-
tion pattern.3 The most successful cases have been report-
ed for trisubstituted olefines3 and, to a less extend, for
disubstituted4. The AH of tetrasubstituted unfunctional-
ized substrates is still underdeveloped. Only four publica-
tions have reported high catalytic performance for certain
substrates,5 being the Pfaltz catalysts the ones that work
under milder conditions and are applicable to more sub-
strates. The discovery of a family of catalysts with a wide
substrate scope remains a central task in AH of unfunc-
tionalized olefins. A desired additional condition is that
the catalyst family should be synthesized from available
starting materials and be easy to handle.
Here we report the first P,N-ligand family (L1-L6,
Scheme 1) that performs well for the Ir-catalyzed AH of
different types of unfunctionalized olefins. From a com-
mon skeleton, the right choice of either a phosphite
group or phophinite group results in ligands that are
suitable for di-, tri- and tetrasubstituted unfunctionalized
olefins. The "ligand family" concept helps to reduce the
time dedicated to ligand design and preparation and facil-
itates the discovery of the optimal ligand for a wide range
of substrates. This family has also been successfully ap-
plied to the AH of challenging functionalized cyclic β-
enamides.6
Figure 1. Representative ligands developed for the Ir-
catalyzed AH of di-, tri- and tetrasubstituted minimally func-
tionalized olefins.5c,7
The new Ir-catalyst precursors [Ir(cod)(L1-L6a-h)]BArF,
with the P,oxazoline ligands were prepared in few steps
from readily available α-acetoxy acids 1-3 (Scheme 1).8
From a common skeleton, several ligand modules can be
independently varied to form the family of catalysts. The
variations include: the substituents and configurations at
the ligand backbone (R1); the substituents and configura-
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tions at the oxazoline (R2); the substituents and configu-
ration of the biaryl phosphite moiety (a-e); and the type
of P-donor group (phosphite or phosphinite). Compounds
1-3, already incorporate the desired diversity in the sub-
stituents at the alkyl backbone chain (R1). Compounds 1-3
were first coupled with the desired chiral amino alcohol
to afford amides 4-9. This step introduced diversity in the
substituents and configuration of the oxazoline moiety
(R2). Compounds 4-9 were then converted to the hydrox-
yl-oxazolines 10-15 by reaction with diethylaminosulfur
trifluoride (DAST) followed by standard acetate deprotec-
tion. Reaction of the hydroxyl-oxazolines with the corre-
sponding phosphorochloridite afforded the phosphite-
oxazoline ligands (L1-L6a-e); the reaction with the chlo-
rophosphine afforded the phosphinite-oxazoline ligands
(L1-L6f-h). Ligand coordination by reaction with 0.5
Table 1. Ir-catalyzed AH of model tri-, di- and tetrasubstitut-
ed minimally functionalized olefins S1–S3.a
1
2
3
4
5
6
7
8
P,N %Co-
nvb
%Co-
nvb
%Co
-nvb
9
% eec
% eec
% eec
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
L1a
L1b
L1c
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
58 (R)
75 (R)
67 (S)
92 (R)
68 (S)
60 (R)
70 (R)
30 (R)
64 (R)
38 (R)
44 (R)
15 (R)
9 (R)
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
96 (S)
88 (S)
40 (S)
93 (S)
42 (S)
81 (S)
82 (S)
95 (S)
89 (S)
80 (S)
84 (S)
54 (S)
97 (S)
77 (S)
98 (R)
74 (R)
92 (R)
85 (R)
83 (R)
85 (R)
92 (S)
92 (S)
10 (S)
96 (S)
91 (S)
60 (S)
39d
14d
25d
22d
36d
100
100
25d
10d
100e
100
100
5d
37 (S,S)
29 (S,S)
16 (S,S)
23 (S,S)
18 (S,S)
84 (S,S)
80 (S,S)
82 (S,S)
50 (S,S)
97 (S,S)
87 (S,S)
75 (S,S)
34 (R,R)
ndf
L1d
L1e
L1f
-
equiv of [Ir(µ-Cl)(cod)]2 followed by in situ Cl-/BArF
counterion exchange led to the desired catalyst precur-
sors [Ir(cod)(L1-L6a-h)]BArF as orange air stable solids.
L1g
L2a
L2b
L2f
L2g
L2h
L3a
L3b
L4a
L4d
L4e
L4f
L4g
L4h
L5a
L5d
L5e
L6a
L6d
88 (R)
76 (S)
0
<5
50d
5d
64 (S,S)
4 (S,S)
93 (S)
71 (S)
66 (S)
80 (S)
78 (R)
98 (R)
40 (S)
81 (R)
94 (R)
30 (R)
24
47 (R,R)
75 (R,R)
70 (R,R)
20 (R,R)
42 (S,S)
25 (S,S)
21 (S,S)
53 (S,S)
12 (S,S)
30 (S,S)
100
100
100
15d
10d
15d
20d
13d
Scheme 1. Synthesis of [Ir(cod)(L1-L6a-h)]BArF catalyst
precursors. (a) SOCl2, DCM, reflux, 3 h; (b) aminoalcohol,
NEt3, DCM, rt, 5 h; (c) DAST, K2CO3, DCM, -78 °C to rt for
3 h; (d) NaOH (aq), EtOH, 0 ºC, 3 h; (e) ClP(OR)2, Py,
toluene, -78 °C to rt, 16 h; (f) ClPR2, NEt3, DMAP, toluene,
rt, 20 min; (g) [Ir(µ-Cl)(cod)]2, DCM, reflux, 1 h then
NaBArF, H2O, rt, 30 min.
L6e
25d
a
Reaction conditions: 1 mol% Ir-catalyst precursor, sub-
strate (0.5 mmol), DCM, rt for 4 h, PH2 = 50 bar (for S1 and
S3), 1 bar (for S2). b Conversions determined by GC. c Enanti-
omeric excesses determined by chiral GC. d Reactions carried
e
f
out for 20 h. Reaction performed at 25 bar H2. not deter-
mined.
[Ir(cod)(L1-L6a-h)]BArF complexes were first evaluated
in the hydrogenation of model di-, tri- and tetrasubstitut-
ed minimally functionalized alkenes (S1-S3; Table 1). For
comparison, catalyst precursors were tested in the opti-
mal reaction conditions reported in previous studies with
other P,N-ligands.3 High enantioselectivities, comparable
to the best ones reported,3 were obtained for all sub-
strates, regardless of the olefin substitution pattern.
The results also reveal several trends in the obtained
enantioselectivities: (i) the highest enantioselectivity in
the reduction of di- and trisubstituted olefins (ee's up to
98%,) were obtained with phosphite-based ligands (eg.
L4a and L5d) while phosphinite-based ligands were re-
quired for tetrasubstituted olefins (cf. L2f vs. L2a, ee's up
to 97%),9 (ii) oxazolines derived from expensive tert-
leucinol (eg. ligands L3) were not needed to achieve high
ees, which is an important advantage over the most wide-
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ly used P-oxazoline ligands (e.g. PHOX-derived ligands);3
ity was high (97% ee) in the AH of one substrate only.
Interestingly the hydrogenation of the latter substrates
can be achieved at only 1 bar of H2. It should be noted
that the more rigid the tretrasubstituted olefin is, the less
bulky phosphinite moieties are required to reach the
maximum enantioselectivity. For the more rigid cyclic
indene derivatives S3 and S45-S50, the best catalytic per-
formance is reached with the phosphinite-based ligand
L2f, while for the less rigid cyclic substrate S51, the phos-
phinite ligand L2g, with a more bulky tolyl group is need-
ed. Finally, the even less rigid acyclic substrates (S52-S56)
require the diastereoisomeric ligand L4h, which has the
bulkiest cyclohexenyl phosphinite group.
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2
3
4
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(iii) finally, for substrates S1 and S2, both enantiomers of
the hydrogenated products were accessible in high enan-
tioselectivities by using diastereoisomeric ligands (e.g.
98% (R) for S1 with L4a vs 96% (S) with L1a; or 93% (S)
for S2 with L4a vs 98 (R) with L5d).
We then performed a broad unfunctionalized substrate
screening that included di-, tri- and tetrasubstituted ole-
fins, different geometries (E and Z), and different neigh-
boring polar groups. A summary of the AH results of 53
olefins is shown in Figure 2 (see S.I. for a complete series
of results). As seen previously, the best results for di- and
trisubstituted olefins were achieved with phosphite-based
ligands and for tetrasubstituted with phosphinite-based
ligands. The other ligand parameters had a different in-
fluence depending on the substrate and had to be specifi-
cally selected to obtain high enantioselectivities.
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For the reduction of minimally unfunctionalized trisub-
stituted olefins, the new catalyst precursors were found to
be well suited for those with E-geometry (S4-S5) and for
those with the challenging Z-geometry (S6) and the exo-
cyclic olefin (S7), obtaining in all cases both enantiomers
of the reduced products. They also worked well for olefins
with a variety of relevant neighboring polar groups such
as α,β-unsaturated esters, ketones and lactames, vinyl
boronates and enol phosphinates (S8-S32). All the sub-
strates were hydrogenated with excellent enantiocontrol
(ee’s up to >99%), comparable to the best ones reported.3
In addition, for each type of neighboring group, the enan-
tioselectivities were quite independent on the electronic
and steric nature of the substituents decorating such
motifs. The effective hydrogenation of such a range of
olefins is of great importance since their reduced prod-
ucts are key structural chiral units found in many high
value chemicals (e.g. α- and β-chiral ketones and carbox-
ylic acid derivatives are ubiquitous in natural products,
fragrances, agrochemicals, and drugs).10
Our catalyst precursors also proved to be highly compe-
tent in the hydrogenation of a broad range of disubstitut-
ed olefins (S33-S45). Excellent enantioselectivities were
achieved (up to >99% ee) in the AH of a series of 1,1-
disubstituted (hetero)aryl/alkyl olefins and also aryl- and
alkyl-enol phosphinates. The reduction α-alkylstyrenes
with less sterically demanding alkyl substituents proceed-
ed with somewhat lower enantioselectivies (see S.I, for
details), like in previous successful reports.4,11
Finally, for tetrasubstituted olefins our catalyst precur-
sors proved to be highly efficient in the reduction of sev-
eral indenes (S46-S50) with different substituents at both
the benzylic and vinylic position as well as substituents in
the aryl ring (ee’s up to 98%), under the comparable mild
reactions conditions developed by Pfaltz.5c This improved
previously reported results. The high enantiocontrol for
the more challenging 3,4-dimehtyl-1,2-dihydronapthalene
and the acyclic tetrasubstituted olefins (S51-S56; ee’s up to
98%), is even more remarkable, surpassing the best re-
sults reported so far. For acyclic substrates, only the
Pfaltz's catalysts have been successful but enantioselectiv-
Figure 2. Selected results for AH of a range of di-, tri- and
tetrasubstituted minimally functionalized olefins. Typical
reaction conditions: 1 mol% of [Ir(cod)(P-N)]BArF, 50 bar H2,
DCM, rt for 4 h. Full conversions were achieved in all cases. a
b
Reactions carried out at 50 bar H2 for 24 h. Reactions car-
c
ried out at 1 bar H2 for 4 h. Reactions carried out at 25 bar
d
e
H2 for 24 h. Reaction carried out at 75 bar H2 for 24 h.
Reactions carried out at 1 bar H2 for 24 h.
Encouraged by these remarkable results, we decided to
study the AH of cyclic β-enamides (Figure 3) which are a
challenging type of functionalized olefins.6 While the
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Notes
Page 4 of 6
reduction of α-enamides can be carried out with good
success,2 the AH of β-enamides remains one of the puz-
zling transformations, albeit the corresponding products
are key units in many drugs and biologically active natu-
ral products such as Rotigotine,12a Alnespirone12b and Rob-
alzotan12c. We found that catalyst precursors with ligands
L4e and L5d provided both enantiomers of the hydrogen-
ated products in high enantioselectivities (ee’s up to 99%)
for a range of cyclic β-enamides, including the less stud-
ied enamides derived from 3-chromanones. These results
are comparable to the best one reported in the literature.6
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2
3
4
5
6
7
8
The authors declare no competing financial interest.
Supporting Information. Preparation, characterization
details and copies of NMR spectra of [[Ir(cod)(L1-L6a-
h)]BArF complexes. General procedure for the asymmetric
hydrogenation. Characterization details and methods for
enantiomeric excess determination of hydrogenated prod-
ucts. Complete series of results for the asymmetric hydro-
genation of unfunctionalized olefins S4-S56 and cyclic β-
enamide S57. Copies of NMR and GC/HPLC traces for all
hydrogenated products. Deuterium labelling experiments.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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ACKNOWLEDGMENT
We gratefully acknowledge financial support from the Span-
ish Ministry of Economy and Competitiveness (CTQ2016-
74878-P),
European
Regional
Development
Fund
(AEI/FEDER, UE), the Catalan Government (2017SGR1472),
and the ICREA Foundation (ICREA Academia award to M.D).
REFERENCES
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(b) Tang, W.; Zhang, X. New Chiral Phosphorus Ligands for
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thesis; Murahashi, S.-I., Ed.; Wiley-VCH, Weinheim, 2004, pp 3–
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ric Hydrogenations of Largely Unfunctionalized Alkenes. Chem.
Rev. 2005, 105, 3272–3296. (b) Roseblade, S. J.; Pfaltz, A. Iridium-
Catalyzed Asymmetric Hydrogenation of Olefins. Acc. Chem.
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Asymmetric Hydrogenation of Alkenes Lacking Coordinating
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J. Am. Chem. Soc. 2017, 139, 1346–1356.
Figure 3. Selected hydrogenation results for the AH of cyclic
β-enamides. Typical reaction conditions:
1
mol% of
[Ir(cod)(P-N)]BArF, 50 bar H2, DCM, rt for 24 h. Full conver-
sions were achieved in all cases.
In summary, we have presented the first Ir-P,oxazoline
catalytic family, with a simple modular architecture, that
is able to successfully hydrogenate di-, tri- and tetrasub-
stituted minimally functionalized olefins (ee's up to 99%).
This family of catalysts has been synthesized in a few
steps from unexpensive starting materials and are solid
and stable in air. From a common skeleton, the right
choice of either a phosphite group or phophinite group
gives ligands that are suitable for di-, tri- and also
tetrasubstituted olefins (62 examples). Improving previ-
ous results reported, these catalysts are able to efficiently
reduce a range of indenes and the challenging 1,2-
dihydro-napthalene (ee’s up to 98%) and also a range of
the most elusive acyclic olefins with unprecedented enan-
tioselectivities (ee’s up to 98%) under mild reaction con-
ditions. The catalysts not only exhibited an unprecedent-
ed high tolerance to the geometry and steric constrains of
the olefin, but they also could tolerate different functional
groups very well. Thus, a broad range of olefins contain-
ing both minimally coordinative groups (e.g. α,β-
unsaturated carboxylic esters, enones, lactames, vinyl
boronates and enol phosphinates) and coordinative
groups (the challenging β-enamides) could be hydrogen-
ated with high levels of enantioselectivity.
ASSOCIATED CONTENT
AUTHOR INFORMATION
Corresponding Author
(4) Pàmies, O.; Andersson, P. G.; Diéguez, M. Asymmetric
Hydrogenation of Minimally Functionalised Terminal Olefins:
An Alternative Sustainable and Direct Strategy for Preparing
Enantioenriched Hydrocarbons. Chem. Eur. J. 2010, 16, 14232–
14240.
* E-mail for O.P.: oscar.pamies@urv.cat
* E-mail for M.D.: montserrat.dieguez@urv.cat
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(5) For successful AH of tetrasubstituted unfunctionalized ole-
lysts for the Highly Enantioselective Hydrogenation of Terminal
fins see: Zr-catalysts; a) Troutman, M. V.; Appella, D. H.; Buch-
wald, S. L. Asymmetric Hydrogenation of Unfunctionalized
Tetrasubstituted Olefins with a Cationic Zirconocene Catalyst. J.
Am. Chem. Soc. 1999, 121, 4916–4917 (ee's in the range 52-99% for
some indene derivatives, at 8 mol% of catalyst and 110 bar of H2).
Rh-PP catalysts. (b) Zhang, Z.; Wang, J.; Li, J.; Yang, F.; Liu, G.;
Tang, W.; He, W.; Fu, J.-J.; Shen, Y.-H.; Li, A.; Zhang, W.-D.
Total Synthesis and Stereochemical Assignment of Delavatine A:
Rh-Catalyzed Asymmetric Hydrogenation of Indene-Type
Tetrasubstituted Olefins and Kinetic Resolution through Pd-
Catalyzed Triflamide-Directed C-H Olefination. J. Am. Chem.
Soc. 2017, 139, 5558–5567 (ee's in the range 85-95% at 10 mol% of
Rh, 60°C in 4 days). Ir-PN catalysts see: (c) Schrems, M. G.;
Neumann, E.; Pfaltz, A. Iridium-Catalyzed Asymmetric Hydro-
genation of Unfunctionalized Tetrasubstituted Olefins. Angew.
Chem. Int. Ed. 2007, 46, 8274–8276 (94-97% ee, 1-2 mol % of Ir at
Alkenes. J. Am. Chem. Soc. 2009, 131, 12344–13353.
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(8) Kazmaier’s group developed
a
related diphe-
nylphosphinite-oxazoline ligand, derived from pivaldehyde and
tert-leucinol (R1=R2= tBu). The Ir-catalyst modified with this
ligand was only efficient in the AH of α,β-unsaturated ketones
(ee’s up to >99%). Thus, it was catalytically inactive for the other
classes of olefins tested (e.g. enol phosphinates, α,β-unsaturated
esters, enamides…). Maurer, F.; Huch, V.; Ullrich, A.; Kazmaier,
U. Development of Catalysts for the Stereoselective Hydrogena-
tion of α,β-Unsaturated Ketones. J. Org. Chem. 2012, 77, 5139–
5143.
(9) A possible reason for this behavior is a higher degree of
isomerization using phosphite-based catalysts than the phos-
phinite analogues which leads to complex mixtures of olefins in
solution. This was observed in preliminary deuteration studies
performed with tetrasubstituted olefins (see Supporting Infor-
mation for details of deuteration experiments). A second possi-
ble reason, based on our previous quadrant analysis of the most
stable TSs with related phosphite-oxazoline ligands, can be
related to the bulkiness of the biaryl phosphite group. This bulk-
iness has shown to be beneficial in generating a well-suited
chiral pocket for di- and trisubstituted olefins; nevertheless for
tetrasubstituted olefins it seems to hamper the preferential
coordination of the substrate, leading to TSs with similar high
energies, which results in low activities and enantioselectivities
(see: Mazuela, J.; Norrby, P.-O; Andersson, P. G.; Pàmies, O.;
Diéguez, M. Pyranoside Phosphite–Oxazoline Ligands for the
Highly Versatile and Enantioselective Ir-Catalyzed Hydrogena-
tion of Minimally Functionalized Olefins. A Combined Theoreti-
cal and Experimental Study. J. Am. Chem. Soc. 2011, 133, 13634–
13645).
(10) See, for instance: (a) Saudan, L. A. Hydrogenation Pro-
cesses in the Synthesis of Perfumery Ingredients. Acc. Chem. Res.
2007, 40, 1309–1319. (b) Etayo, P.; Vidal-Ferran, A. Rhodium-
Catalysed Asymmetric Hydrogenation as a Valuable Synthetic
Tool for the Preparation of Chiral Drugs. Chem. Soc. Rev. 2013,
42, 728–754. (c) Fürstner, A.; Bindl, M. Concise Total Synthesis of
Cruentaren A. Angew Chem. Int. Ed. 2007, 46, 9275–9278.
(11) For the successful AH of disubstituted olefins, see: (a)
Blankenstein, J.; Pfaltz, A. A New Class of Modular Phosphinite–
Oxazoline Ligands: Ir-Catalyzed Enantioselective Hydrogenation
of Alkenes. Angew. Chem. Int. Ed. 2001, 40, 4445–4447. (b) McIn-
tyre, S.; Hörmann, E.; Menges, F.; Smidt, S. P.; Pfaltz, A. Iridi-
um-Catalyzed Enantioselective Hydrogenation of Terminal
Alkenes. Adv. Synth. Catal. 2005, 347, 282-288. (c) Biosca, M.;
Paptchikhine, A.; Pàmies, O.; Andersson, P. G.; Diéguez, M.
Extending the Substrate Scope of Bicyclic P-Oxazoline/Thiazole
Ligands for Ir-Catalyzed Hydrogenation of Unfunctionalized
Olefins by Introducing a Biaryl Phosphoroamidite Group. Chem.
Eur. J. 2015, 21, 3455-3464.
(12) (a) Pharm, D. Q.; Nogid, A. Rotigotine Transdermal Sys-
tem for the Treatment of Parkinson's Disease. Clin. Ther. 2008,
30, 813-824. (b) Astier, B.; Lambás Señas, L.; Soulière, F.; Schmitt,
P.; Urbain, N.; Rentero, N.; Bert, L.; Denoroy, L.; Renaud, B.;
Lesourd, M.; Muñoz, C.; Chouvet, G. In vivo Comparison of Two
5-HT1A Receptors Agonists Alnespirone (S-20499) and Buspi-
rone on Locus Coeruleus Neuronal Activity. Eur. J. Pharmacol.
2003, 459, 17–26. (c) Ross, S. B.; Thorberg, S.-O.; Jerning, E.;
Mohell, N.; Stenfors, C.; Wallsten, C.; Milchert, I. G.; Ojteg, G. A.
Robalzotan (NAD-299), a Novel Selective 5-HT 1A Receptor
Antagonist. CNS Drug Rev. 1999, 5, 213-232.
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r.t). (d) Busacca, C. A.; Qu, B.; Grět, N.; Fandrick, K. R.; Saha, A.
K.; Marsini, M.; Reeves, D.; Haddad, N.; Eriksson, M.; Wu, J. P.;
Grinberg, N.; Lee, H.; Li, Z.; Lu, B.; Chen, D.; Hong, Y.; Ma, S.;
Senanayake, C. H. Tuning the Peri Effect for Enantioselectivity:
Asymmetric Hydrogenation of Unfunctionalized Olefins with
the BIPI Ligands. Adv. Synth. Catal. 2013, 355, 1455–1463 (ee's up
to 96% at 0°C for two substrates).
(6) For the most successful applications see: a) Jiang, X.-B.;
Lefort, L.; Goudriaan, P. E.; de Vries, A. H. M.; van Leeuwen, P.
W. N. M.; Reek, J. N. H. Screening of a Supramolecular Catalyst
Library in the Search for Selective Catalysts for the Asymmetric
Hydrogenation of a Difficult Enamide Substrate. Angew. Chem.
Int. Ed. 2006, 45, 1223–1227. (b) Wu, Z.; Ayad, T.; Ratoveloma-
nana-Vidal, V. Efficient Enantioselective Synthesis of 3-
Aminochroman Derivatives Through Ruthenium-Synphos Cata-
lyzed Asymmetric Hydrogenation. Org. Lett. 2011, 13, 3782–3785.
(c) Liu, G.; Liu, X.; Cai, Z.; Jiao, G.; Xu, G.; Tang, E. Design of
Phosphorus Ligands with Deep Chiral Pockets: Practical Synthe-
sis of Chiral β-Arylamines by Asymmetric Hydrogenation. An-
gew. Chem. Int. Ed. 2013, 52, 4235–4238. (d) Salom, E.; Orgué, S.;
Riera, A.; Verdaguer, X. Highly Enantioselective Iridium-
Catayzed Hydrogenation of Cyclic Enamides. Angew. Chem. Int.
Ed. 2016, 55, 7988–7992. (e) Magre, M.; Pàmies, O.; Diéguez, M.
PHOX-Based Phosphite-Oxazoline Ligands for the Enantioselec-
tive Ir-Catalyzed Hydrogenation of Cyclic β-Enamides. ACS
Catal. 2016, 6, 5186–5190. (f) Li, X.; You, C.; Yang, H.; Che, J.;
Chen, P.; Yang, Y.; Lv, H.; Zhang, X. Rhodium-Catalyzed Asym-
metric Hydrogenation of Tetrasubstituted Cyclic Enamides:
Efficient Access to Chiral Cycloalkylamine Derivatives. Adv.
Synth. Catal. 2017, 359, 597–602. (g) Tang, W.; Wu, S.; Zhang, X.
Enantioselective Hydrogenation of Tetrasubstituted Olefins of
Cyclic β-(Acylamino)acrylates. J. Am. Chem. Soc. 2003, 125, 9570–
9571.
(7) (a) Kaiser, S.; Smidt, S. P.; Pfaltz, A. Iridium Catalysts with
Bicyclic Pyridine–Phosphinite Ligands: Asymmetric Hydrogena-
tion of Olefins and Furan Derivatives. Angew. Chem. Int. Ed.
2006, 45, 5194–5197. (b) Li, S.; Zhu, S.-F.; Xie, J.-H.; Song, S.;
Zhang, C.-M.; Zhou, Q.-L. Enantioselective Hydrogenation of α-
Aryloxy and α-Alkoxy α,β-Unsaturated Carboxylic Acids Cata-
lyzed by Chiral Spiro Iridium/Phosphino-Oxazoline Complexes.
J. Am. Chem. Soc. 2010, 132, 1172–1179. (c) Källström, K.; Hedberg,
C.; Brandt, P.; Bayer, P.; Andersson, P. G. Rationally Designed
Ligands for Asymmetric Iridium-Catalyzed Hydrogenation of
Olefins. J. Am. Chem. Soc. 2004, 126, 14308–14309. (d) Mazuela,
J.; Verendel, J. J.; Coll, M.; Schäffner, B.; Börner, A.; Andersson, P.
G.; Pàmies, O.; Diéguez, M. Iridium Phosphite−Oxazoline Cata-
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ee's typically 95-99%
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